1. Technical Field
The present invention relates generally to a method for imparting antimicrobial activity to a medical device. More particularly, the invention relates to a method for imparting broad spectrum antimicrobial activity by sequentially contacting a medical device with a first antimicrobial component, such as an antiseptic, and a second antimicrobial component, such as a mixture of antibiotics.
2. Background Information
Indwelling medical devices, such as central venous catheters (CVCs), have now become essential tools for use by the medical professional when addressing present-day medical disorders. The benefits derived from these catheters, as well as other indwelling medical devices such as peritoneal catheters, cardiovascular devices, orthopedic implants, penile implants, and other prosthetic devices, have enabled the medical professional to address disorders that had not previously been possible to address by conventional means, or that could only be addressed in a limited manner.
Recent estimates suggest that more than 5 million CVCs are now inserted into patients each year in the United States, with an estimate of 15 million CVC days in intensive care units (ICUs) (the total number of days of exposure to CVCs by all patients in the selected population during the selected time period). However, the use of CVCs is sometimes complicated by catheter-related bloodstream infections (CRBSIs). Colonization of microbials on the surface or other parts of the catheter can produce serious patient problems, including the need to remove and/or replace the CVC, and to vigorously treat any resulting infective conditions.
Reports have shown that between 250,000 and 400,000 vascular catheter-related bacteremias and fungemias occur annually in the United States. Such infections can be life-threatening, and are generally difficult to treat. Approximately 80,000 CRBSIs occur in ICUs, with an average of 5.3 CRBSIs per 1,000 catheter days in the ICU. It is estimated that the mortality rate attributable to CVC infections ranges from about 12 to 25% in critically ill patients, with an increased in-hospital stay ranging from 10 to 20 days, and an added cost ranging from about $4,000 to $56,000 per episode. Almost 70% of CRBSIs are caused by gram-positive organisms, particularly staphylococci such as coagulase negative staphylococci and Staphylococcus aureus. 
A considerable amount of attention and study has been directed toward preventing microbial colonization. On some occasions, an antimicrobial agent, such as an antibiotic, is coated on the surface of the catheter in an attempt to produce a sufficient bacteriostatic or bactericidal action to reduce or prevent colonization. One early method for preventing bacterial colonization involved coating the catheter with vancomycin. Vancomycin was considered an antibiotic of choice for treating systemic staphylococcal infections, particularly methicillin resistant S. epidermidis and S. aureus. However, although vancomycin exhibits activity against nonadherent staphylococci in vitro and in human tissue, it is not generally active against staphylococci of the type that adhere to foreign bodies and embed themselves in a layer of biofilm. It is believed that biofilm (slime or fibrous glycocalix) acts as a shield to protect the adherent staphylococci from vancomycin, and to inhibit the activity of glycopeptide antibiotics (vancomycin and teicoplanin). In addition, prophylactic use of vancomycin on a highly colonized surface (such as a catheter) was disfavored for fear that it would promote the emergence of vancomycin resistant staphylococci. Additionally, vancomycin had no activity on fungi, such as Candida albicans. 
Other investigations into catheter-associated infections showed that bacterial-produced adherent biofilms promote staphylococcal and Pseudomonas tolerance to antibiotics normally effective against the same bacteria systemically or in tissue. Evidence of this problem was demonstrated by the inability of tobramycin to kill Pseudomonas aeruginosa cells embedded in a biofilm at antibiotic levels of greater than 50 times the minimum bactericidal concentration (MBC) for the identical strain grown in liquid suspension. Nickel et at, Antimicrob. Agents Chemother. 27:619-624 (1985). All publications and patent documents referred to throughout this document are incorporated by reference in their entirety. Similarly, six weeks of intensive antibacterial chemotherapy with a β-lactam antibiotic, to which laboratory cultures were exquisitely sensitive, failed to prevent frequent recurrences of a S. aureus bacteremia originating from an endocardial pacemaker. Direct examination of the tip of the pacemaker lead revealed that the staphylococci grew in thick slimed enclosed biofilm, which protected the bacteria from very high tissue levels of antibiotic. Subsequent in vitro studies showed the biofilm adherent bacteria were resistant to levels of antibiotics 50 to 100 times higher than the MBC needed to kill non-biofilm encased cells of the same strain. Khoury, A. E. and Costeron J. W., “Bacterial Biofilms in Nature and Disease”, Dialogues in Pediatric Urology, Vol. 14:2-5 (1991).
Another known method for coating implantable devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride, followed by ionic bonding of the antibiotic composition. See, e.g., Solomon, D. D. and Sherertz, R. J., J. Controlled Release, 6:343-352 (1987), and U.S. Pat. No. 4,442,133. Other methods have involved coating a catheter with the antiseptic composition chlorhexidine (CHX), either alone, or in combination with silver sulfadiazine (CHSS). Still other known methods have involved the initial application or absorption on the surface of the medical device of a layer of tridodecylmethyl ammonium chloride (TDMAC) surfactant, followed by an antibiotic coating layer.
Numerous patents describe other methods of coating medical devices with antibiotics. These patents include U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pKa of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders).
Although the methods described in the above-cited references have demonstrated various levels of success in minimizing the extent of bacterial infection, the spectrum of protection available has often been less than desired, and the period of time with which the protection continues has also often been less than desired.
U.S. Pat. No. 5,217,493 teaches an implantable medical device wherein the surface of the device was coated with an antimicrobial composition comprising a combination of antibiotics, such as the antibiotics minocycline and rifampin (M/R). According to the '493 patent, this antimicrobial combination was found to be very effective in killing biofilm-associated staphylococci, particularly Staphylococcus epidermidis and Staphylococcus aureus, when applied to the surface of an indwelling medical device. The antimicrobial composition was found to be particularly effective with regard to its activity against methicillin-sensitive and resistant staphylococci, and to exhibit broad spectrum inhibitory activity against other gram-positive organisms, such as enterococci, Corynebacterium and Bacillus species. It has been estimated that this antimicrobial composition exhibited favorable activity against resistant staphylococci of the type that account for about 60-70% of CRBSIs.
Although indwelling devices coated with antimicrobial compositions, such as the antimicrobial combinations described in the '493 patent, have generally exhibited effective protection against specified bacteria upon initial implantation, the effectiveness of the protection was subject to diminution over time. During use of the device, the antimicrobial composition may leach from the surface of the device into the surrounding tissue. Over a period of time, the amount of antimicrobials remaining in the device may diminish to an extent that the device no longer provides an optimal level of protection.
U.S. Pat. No. 5,624,704 teaches a medical implant that is impregnated with an antimicrobial, or an antimicrobial combination, such as the minocycline and rifampin (M/R) combination disclosed in the '493 patent. Impregnating the medical implant with these antimicrobials, rather than coating the implant as described in the '493 patent, provided protection for a period of time that in many instances exceeded the duration of protection provided by the coated catheters.
The antimicrobial coated and impregnated catheters disclosed in the '493 and '704 patents demonstrated marked improvement in antimicrobial activity when compared to other commercially available catheters. In vitro and animal studies have shown that M/R coated and impregnated catheters exhibited superior and more prolonged activity against staphylococci when compared with the CHSS-coated catheters described above. In serum at 37° C., the half-life of the antimicrobial activity against S. epidermidis of CHSS-coated catheters was 3 days versus 25 days for the M/R-impregnated catheters, with a zone of inhibition ≧15 mm after 30 days of incubation. For other gram-positive organisms that are commonly associated with CRBSIs (e.g., S. epidermidis, S. aureus, Corynebactertiumi), the mean zone of inhibition was 31.
Another study demonstrated the benefits of M/R-impregnated catheters against catheter-related microbial pathogens when compared to existing antimicrobial catheters. According to this study, after 28 days of being soaked in serum, CVCs impregnated with CHSS, and CVCs impregnated with silver, platinum, and carbon had lost antimicrobial activity against methicillin-resistant S. aureus (MRSA) within 14 days. To the contrary, CVCs impregnated with M/R maintained their activity against MRSA for at least 28 days. Hanna H, et al., “Comparative in vitro efficacies and antimicrobial durabilities of novel antimicrobial central venous catheters.” Antimicrob. Agents Chemother., 50(10): 3283-8 (2006).
Still another study showed that M/R-coated catheters exhibited significant protection and reduction of staphylococcal adherence, as well as more prolonged antimicrobial durability, against vancomycin-resistant S. aureus (VRSA), Stenotrophomonas maltophilia and Acinetobacter spp. when compared to CHSS and silver, platinum and carbon (SPC) coated catheters, as well as against uncoated catheters. M/R-coated CVCs and CHSS-coated CVCs showed comparable anti-adherence and antimicrobial durability against multi-drug resistant Enierobacter agglomerans, but were superior to the SPC and the uncoated catheters. (Hachem R, Chemaly R F, Jiang Y, Reitzel R, Dvorak T, Raad I. Anti-adherence activity and antimicrobial durability of anti-infective-coated catheters against multidrug-resistant (MDR) bacteria. IN: Proceedings of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Ill. (Sep. 17-20, 2007)).
Although the antimicrobial-coated and impregnated catheters of the '493 and '704 patents demonstrated marked improvement over other commercially-available catheters, some challenges have persisted. For example, even though the minocycline and rifampin combination demonstrated antimicrobial activity against resistant staphylococci, as well as some resistant gram negative bacteria, the M/R antimicrobial combination did not exhibit significant activity against Pseudomonas aeruginosa, and against fungi such as Candida parapsilosis, Candida albicans and the more resistant Candida krusei. (Hanna H, et al, supra.) Pseudomonas aeruginosa is considered the most virulent gram negative bacteria causing catheter-related bacteremia. Candida parapsilosis, Candida albicans and Candida krusei have been implicated in causing catheter-related Candidemia, which is associated with very high rates of morbidity and mortality.
A need persists for a method for providing efficacious broad spectrum anti-infective protection to a medical device, including but not limited to, protection against resistant staphylococci, MDR gram negative bacteria (such as MDR Pseudomonas aeruginosa), and resistant Candida (e.g., C. krusei).